据悉，Fasenra是阿斯利康第二畅销的呼吸和免疫药物。2025年上半年，该药销售额达9.2亿美元，同比 增长18%。参与Fasenra试验的患者均为现吸烟者或曾经吸烟者，他们正在接受现有治疗，并且在前一年 至少有两次急性发作史。阿斯利康表示，与安慰剂相比，Fasenra未能在研究中达到主要终点，并补充 称将对完整的研究数据进行分析，以更好地理解结果。 资料显示，Fasenra是阿斯利康开发的一款首创IL-5Rα单抗，目前已在美国、日本、欧盟和中国等80多 个国家获批作为重度嗜酸性粒细胞性哮喘(SEA)的附加维持治疗，并在美国和日本获批用于6岁及以上 儿童及青少年的SEA治疗。该药物还在60多个国家获批用于治疗成人嗜酸性肉芽肿性多血管炎 (EGPA)，目前针对高嗜酸性粒细胞综合征(HES)的适应症正在接受监管审评。 阿斯利康高管Sharon Barr表示："COPD仍是全球主要死因之一，它是一种复杂且异质性的疾病。我们将 继续推进研发管线中其他有前景的方案，以满足患者尚未被满足的需求。"该公司治疗COPD的其他药 物包括其三合一吸入剂Breztri Aerosphere，以及在研药物tozorakimab。 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 细胞内核酸感知通路在抵御外部病原体、组织损伤及修复方面发挥着至关重要的作用。位于内体中的 TLR7 和 TLR9 对于感知 RNA 和 DNA 至关重要，对系统性 红斑狼疮 （SLE） 的发展也发挥着关键作用。它们通过识别内源性或外源性核酸，启动下游炎症信号通路 （例如 IFN、NF-κB 和 MAPK） 。在浆细胞样树突状 细胞 （pDC） 中，TLR7 和 TLR9 通路的激活会导致大量干扰素 （IFN） 的释放，促进自身抗原的呈递以及炎症反应的发生。在 B 细胞中，这两条通路的激活均 会导致大量靶向核酸的自身抗体的产生，从而促发系统性红斑狼疮。 PLD4 在树突状细胞、单核细胞和 B 细胞中高度表达。这是一种定位于内体-溶酶体的 5' 核酸外切酶，能够切割单链 RNA （ssRNA） 和单链 DNA （ssDNA） ，从而限制 TLR7 和 TLR9 的过度激活。 Pld4 基因敲除小鼠表现出一系列自身免疫表型，包括体重减轻、脾脏增大、自身抗体增多以及免疫复合物沉积增加。此 外，同时缺乏 Pld4 及其家族成员 Pld3 的小鼠在生命早期就会死亡。 尽管之前的研究 ...

浙江大学良渚实验室、国家肾脏疾病临床医学研究中心刘志红院士，浙江大学良渚实验室俞晓敏研究 员，以及浙江大学良渚实验室、浙江大学生命科学研究院周青教授为论文共同通讯作者。 据介绍，系统性红斑狼疮是一种异质性很强的自身免疫疾病，不管是临床症状还是遗传机制，都存在很 大的个体化差异。这对认识其发病机制构成了极大挑战。 研究团队通过全外显子组测序，发现5例系统性红斑狼疮肾炎患者存在PLD4基因突变，这种基因存在于 人体树突状细胞、B细胞和单核细胞中，PLD4基因突变属于隐性遗传。 新华社杭州9月11日电（记者朱涵）系统性红斑狼疮是一种常见的慢性自身免疫疾病，发病机制复杂。 我国科学家证实，人类单基因（PLD4）的缺陷可导致系统性红斑狼疮，为系统性红斑狼疮的精准诊疗 提供了重要理论依据。该成果10日发表在《自然》杂志上。 研究团队进一步发现，这一基因突变引发了机体长期炎症及自身免疫的致病机制，并通过小鼠实验证 实，某些靶向治疗药物JAK抑制剂可显著缓解缺陷小鼠体重下降、自身抗体产生及组织炎症等症状，可 为携带PLD4突变的系统性红斑狼疮患者提供潜在的精准治疗策略，也为未来开展基于基因分型的个体 化治疗提供了重要依据。（ ...

Core Viewpoint - The research highlights a significant breakthrough in the use of allogeneic CAR-T cell therapy for treating autoimmune diseases, specifically refractory systemic lupus erythematosus (SLE), demonstrating long-term remission and safety [2][3][4]. Group 1: Research Findings - The study published in Cell reported the successful use of allogeneic CD19-targeted CAR-T cells (TyU19) in treating refractory immune-mediated necrotizing myopathy and diffuse cutaneous systemic sclerosis, achieving long-term remission [1]. - In a subsequent study published in Med, the same CAR-T cell therapy was shown to effectively treat three patients with refractory SLE, leading to significant reductions in serum autoantibodies and achieving clinical remission as defined by the SRI-4 standard [3][6][7]. - The therapy demonstrated good tolerance, with no occurrences of graft-versus-host disease (GvHD), cytokine release syndrome (CRS), or immune effector cell-associated neurotoxicity syndrome (ICANS) reported during the study [9][10]. Group 2: Methodology and Safety - The clinical trial involved three patients with severe refractory SLE, where CAR-T cells were infused at a dose of 1 million cells per kilogram, and safety was assessed through the monitoring of potential adverse events [5][6]. - The CAR-T cells showed robust in vivo proliferation, peaking on day 14 post-infusion, and effectively eliminated B cells from the patients, leading to a significant decrease in B cell counts [6][9]. - The study utilized a low-intensity lymphocyte-depleting regimen, and even without pre-treatment lymphocyte clearance, TyU19 exhibited remarkable therapeutic efficacy, indicating a new potential pathway for treating autoimmune diseases [11].

Core Viewpoint - The study demonstrates the safety and efficacy of allogeneic CD19-targeted CAR-T cell therapy (TyU19) in treating refractory systemic lupus erythematosus (SLE), marking a significant advancement in the application of CAR-T cell therapy for autoimmune diseases [2][3][16]. Group 1: Research Background - In 2021, researchers at Erlangen-Nuremberg University successfully treated a patient with refractory SLE using CAR-T cell therapy, leading to numerous clinical trials worldwide to evaluate its safety and efficacy in B cell-mediated autoimmune diseases [2]. - Allogeneic CAR-T cells offer advantages such as uniformity, rapid availability, and potential cost-effectiveness, but face limitations due to risks like graft-versus-host disease (GvHD) and gene editing-related toxicity [2][3]. Group 2: Study Details - The study, a single-center pilot trial (NCT05988216), assessed the safety and efficacy of TyU19 in patients with refractory SLE, utilizing CRISPR-Cas9 gene editing to modify CAR-T cells from healthy donors [6][12]. - Four young female patients aged 22-24 with a history of multiple organ involvement were included, all having baseline SELENA-SLEDAI scores between 14-26 [7]. Group 3: Treatment Protocol and Results - Patients underwent a lymphocyte-depleting chemotherapy regimen before receiving a dose of 1×10^6 CAR-T cells/kg [7]. - All patients showed sustained clinical improvement, achieving a SELENA-SLEDAI score of zero and a PGA score of less than 1 within 3-6 months post-treatment [9][11]. - Symptoms such as arthritis, hair loss, and finger vasculitis resolved, and levels of complement factors C3 and C4 normalized [9]. Group 4: Safety Profile - The most common grade 3 or 4 adverse events included neutropenia, lymphopenia, and liver dysfunction, attributed to the lymphocyte-depleting pre-treatment [11]. - No patients experienced severe adverse events like immune effector cell-associated neurotoxicity syndrome (ICANS) or GvHD, and no infections occurred during the study [11][12]. Group 5: Innovative Aspects - TyU19 demonstrated a significant innovation by requiring a less intensive lymphocyte-depleting regimen compared to traditional CAR-T therapies, even exploring a "no depletion" approach [12]. - The therapy showed potential for long-term efficacy by targeting both abnormal B cells and inhibiting plasma cell regeneration, as evidenced by the reduction of BCMA+ and CD19-BCMA+ plasma cells post-treatment [15][16]. Group 6: Conclusion and Future Directions - The study highlights the potential of allogeneic CD19-targeted CAR-T cell therapy as a promising treatment for refractory SLE, warranting further research to explore its long-term efficacy and optimize its application in challenging autoimmune diseases [16].